Adventitial Fibrosis and Fibroblast Mechanosensitivity Are Shaped by Sex and Hormonal Status in Pulmonary Arterial Hypertension

TL;DR

This study shows that sex and hormones influence fibrosis in pulmonary arterial hypertension, with fibroblast sensitivity to mechanical forces offering a new treatment target.

Contribution

The study reveals that fibroblast mechanosensitivity is modulated by sex and hormones, offering a novel therapeutic angle for PAH.

Findings

Adventitial fibrosis in PAH differs between sexes and is influenced by hormonal status.

Fibroblasts from intact females require higher stiffness to activate fibrotic genes, suggesting hormone-dependent thresholds.

Stretch-induced ECM changes are more prominent in male-derived fibroblasts.

Abstract

What are the main findings?
SuHx-induced pulmonary hypertension produced sex- and hormone-dependent adventitial fibrosis, driven by distinct mechanosensitivity profiles in pulmonary artery adventitial fibroblasts.In vitro hormone-dependent stiffness activation threshold, persistent transcriptional reprogramming after hormone loss, and chromosome-linked stretch responsiveness.

SuHx-induced pulmonary hypertension produced sex- and hormone-dependent adventitial fibrosis, driven by distinct mechanosensitivity profiles in pulmonary artery adventitial fibroblasts.

In vitro hormone-dependent stiffness activation threshold, persistent transcriptional reprogramming after hormone loss, and chromosome-linked stretch responsiveness.

What is the implication of the main finding?
Fibroblast mechanosensitivity as a novel target for stage- and sex-specific PAH therapies.

Fibroblast mechanosensitivity as a novel target for stage- and sex-specific PAH therapies.

Pulmonary arterial hypertension (PAH) is marked by vascular remodeling, yet the role of adventitial fibrosis—and its modulation by sex and hormonal status—remains unclear. We examined stage-specific adventitial remodeling and pulmonary artery adventitial fibroblast (PAAF) mechanosensitivity in male, ovary-intact female, and ovariectomized (OVX) female Sprague–Dawley rats with SuHx-induced PAH. Hemodynamics, pulmonary artery histology, and adventitia-specific transcriptional profiling were integrated with in vitro assays of PAAFs exposed to defined substrate stiffness and stretch. All groups developed comparable increases in mean pulmonary arterial pressure, but vascular resistance shift and adventitial fibrosis diverged by sex: intact females showed attenuated increase in pulmonary vascular resistance and transient collagen accumulation, whereas OVX females mirrored the sustained, male-like progression. Extracellular matrix (ECM) gene activation occurred without smooth muscle actin induction, suggesting noncanonical fibrotic pathways. In vitro, intact female PAAFs required higher substrate stiffness to induce profibrotic gene expression, indicating a hormone-modulated stiffness threshold. OVX PAAFs showed persistent transcriptional reprogramming, while stretch-induced ECM upregulation occurred predominantly in male-derived PAAFs. These findings demonstrate that adventitial fibrosis in PAH is shaped by both hormonal and chromosomal sex, independent of hemodynamic severity, and highlight fibroblast mechanosensitivity as a potential target for stage- and sex-specific interventions.

Figures